Non-steroidal anti-inflammatory drugs (NSAID) are generally used for treatment of acute pain, inflammatory pain, visceral pain, breakthrough pain, nociceptive pain, neuropathic pain, dysmenorrhea, post-surgical pain, acute postpartum pain, postoperative pain management chronic pain in osteoarthritis, rheumatoid arthritis and pain due to other diseases and causes.
Most of the NSAIDs are administered orally. However, parenteral drug formulations have become very important particularly for drugs having analgesic, anti-inflammatory or antipyretic effects. Parenteral routes of administration, including subcutaneous, intramuscular, intrathecal, epidural and intravenous injection, offer numerous benefits over oral delivery. For example, parenteral administration of a drug typically results in attainment of a therapeutically effective blood concentration of the drug in a shorter time than is achievable by oral administration. This is especially true for intravenous injection, whereby the drug is placed directly into the bloodstream. Parenteral administration can also result in more predictable blood serum concentrations of a drug, because drug loss in the gastrointestinal tract due to absorption, distribution, metabolism, binding to food, and other causes is eliminated. Parenteral administration is the preferred method of drug delivery in emergency situations, and is also useful in treating subjects who are uncooperative, unconscious, or otherwise unable or unwilling to accept oral medication.
Acute pain is managed with a variety of drugs including opioid analgesics, e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine; acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs) e.g., ketoprofen, ibuprofen, naproxen, tiaprofenic acid, aceclofenac, diclofenac, piroxicam, loxaprofen, fenoprofen, flurbiprofen, tenoxicam, lornoxicam, acetylsalicylic acid, flufenamic acid, mefenamic acid, nifluniic acid, tolfenamic acid, diflunisal, etodolac, fenbufen, isoxicam, pirprofen, sulindac, tolmetin, and piketoprofen and cyclo-oxygenase isoform 2 (COX-2) selective NSAIDs, e.g., celecoxib, valdecoxib, piketoprofen, etoricoxib, rofecoxib, and lumiracoxib.
Celecoxib is approved in U.S under brand name CELEBREX® capsules and used in the treatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain, chronic pain, primary dysmenorrhea and familial adenomatous polyposis.
Celecoxib was described in U.S. Pat. No. 5,466,823 assigned to Searle, a class of 1,5-diaryl pyrazoles and their salts together with processes for the preparation of such compounds.
Celecoxib is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and is a diaryl-substituted pyrazole. The empirical formula is C17H14F3N3O2S, and the molecular weight is 381.38; the chemical structure is as follows:

Celecoxib is a hydrophobic and highly permeable drug belonging to class Il of biopharmaceutics classification system. Celecoxib is a neutral molecule that is essentially insoluble in water which leads to high variability in absorption and hence has dissolution rate limited bioavailability after oral administration. It also has pre-systemic metabolism. Peak plasma levels of celecoxib occurs approximately 3 hrs after an oral dose.
In acute pain, as in the case of surgical pain, trauma, pain due to kidney stones, and arthritis, which demands immediate relief parenteral route (injection, IV, etc.) is more efficient and prompt, as compared to the oral route.
The process of developing stable parenteral dosage forms for selective COX-2 inhibitors is challenging because of, amongst other things, low physical stability. Attempts have been made to formulate parenteral dosage forms for COX-2 inhibitors as lyophilized powders for reconstitution.
U.S. Pat. No. 6,589,557, assigned to Acusphere describes porous matrices of celecoxib with an enhanced rate of dissolution. The porous matrix may be reconstituted with an aqueous medium and administered parenterally.
U.S. Pat. No. 7,695,736 relates to parenterally deliverable formulations of water-soluble selective COX-2 inhibitory drugs and salts and prodrugs thereof. The invention describes dosage forms that are prepared as lyophilized powders for reconstitution.
U.S. Pat. No. 6,589,973 describes a clear stable pharmaceutical preparation of selective COX-2 inhibitors preferably in the parenteral form. It discloses that injectable formulations of COX-2 inhibitors can be obtained only when dissolved in a selective isosorbide type solvent.
U.S. Pat. Nos. 6,451,339 and 6,383,471 disclose compositions and methods for improved delivery of hydrophobic agents.
U.S. Application No. 2005/0191343 discloses reverse micellar formulations for the delivery of hydrophobic or lipophilic compounds, particularly therapeutic compounds.
PCT Publication WO 2008/077823 discloses self-microemulsifying drug delivery systems and microemulsions used to enhance the solubility of pharmaceutical ingredients comprising a polyoxyethylene sorbitan fatty acid ester emulsifier; a fatty acid ester co-emulsifier and oil.
U.S. Pat. No. 5,496,818 discloses a stable emulsion of the oil-in-water type with a phospholipid as emulsifier and the disperse phase have a positive zeta potential of at least +15, but preferably +30, mV after dilution of the emulsion ready for administration.
U.S. Pat. No. 6,007,826 discloses a cationic oil-in-water emulsion which comprises colloid particles in which a part of the surface-active agents or lipids in the interfacial film have positively charged polar groups, therefore the colloid particles having a positive zeta potential.
U.S. Pat. No. 8,298,568 discloses oil-in-water emulsion useful as a delivery vehicle of hydrophobic ingredients such as pharmaceutical drugs, wherein the emulsion particles have a net positive charge and comprises 0.001 to 0.1% of a cationic agent, 0 to 1% of a non-ionic emulsifier and 0 to 0.5% of an anionic emulsifier.
PCT Publication WO 2008/113177 discloses various compounds and compositions comprising polyunsaturated fatty acid monoglycerides and derivatives thereof.
There remains a long felt need to develop a parenteral composition for NSAID, especially for celecoxib that can be quite useful in acute conditions, such as post-operative pain, acute lower back pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor, pain resulting from burns, including sunburn, post-partum pain, genitourinary tract related pain including cystitis, and the nociceptive pain or nociception, and the like.
The present application relates to a parenteral composition for celecoxib or its pharmaceutically acceptable salts thereof, in the nanoemulsion form.